Ellence

CLINICAL PHARMACOLOGY

Mechanism Of Action

Epirubicin is an anthracycline cytotoxic agent. Although it is known that anthracyclines can interfere with a
number of biochemical and biological functions within eukaryotic cells, the
precise mechanisms of epirubicin's cytotoxic and/or antiproliferative
properties have not been completely elucidated.

Epirubicin forms a complex with
DNA by intercalation of its planar rings between nucleotide base pairs, with
consequent inhibition of nucleic acid (DNA and RNA) and protein synthesis.

Such intercalation triggers DNA
cleavage by topoisomerase II, resulting in cytocidal activity. Epirubicin also
inhibits DNA helicase activity, preventing the enzymatic separation of
double-stranded DNA and interfering with replication and transcription.
Epirubicin is also involved in oxidation/reduction reactions by generating
cytotoxic free radicals. The antiproliferative and cytotoxic activity of
epirubicin is thought to result from these or other possible mechanisms.

Epirubicin is cytotoxic in
vitro to a variety of established murine and human cell lines and primary cultures
of human tumors. It is also active in vivo against a variety of murine tumors
and human xenografts in athymic mice, including breast tumors.

Pharmacokinetics

Epirubicin pharmacokinetics are
linear over the dose range of 60 to 150 mg/m² and plasma clearance
is not affected by the duration of infusion or administration schedule.
Pharmacokinetic parameters for epirubicin following 6-to 10-minute, single-dose
intravenous infusions of ELLENCE at doses of 60 to 150 mg/m² in
patients with solid tumors are shown in Table 4. The plasma concentration
declined in a triphasic manner with mean half-lives for the alpha, beta, and
gamma phases of about 3 minutes, 2.5 hours, and 33 hours, respectively.

aAdvanced solid tumor cancers, primarily of the lung bN=6 patients per dose level cPlasma concentration at the end of 6 to 10 minute infusion dArea under the plasma concentration curve eHalf-life of terminal phase fPlasma clearance gSteady state volume of distribution

Distribution

Following intravenous
administration, epirubicin is rapidly and widely distributed into the tissues.
Binding of epirubicin to plasma proteins, predominantly albumin, is about 77%
and is not affected by drug concentration. Epirubicin also appears to
concentrate in red blood cells; whole blood concentrations are approximately
twice those of plasma.

Metabolism

Epirubicin is extensively and
rapidly metabolized by the liver and is also metabolized by other organs and
cells, including red blood cells. Four main metabolic routes have been
identified:

(1) reduction of the C-13
keto-group with the formation of the 13(S)-dihydro derivative, epirubicinol;
(2) conjugation of both the unchanged drug and epirubicinol with glucuronic
acid; (3) loss of the amino sugar moiety through a hydrolytic process with the
formation of the doxorubicin and doxorubicinol aglycones; and (4) loss of the
amino sugar moiety through a redox process with the formation of the
7-deoxy-doxorubicin aglycone and 7-deoxy-doxorubicinol aglycone. Epirubicinol
has in vitro cytotoxic activity one-tenth that of epirubicin. As plasma levels
of epirubicinol are lower than those of the unchanged drug, they are unlikely
to reach in vivo concentrations sufficient for cytotoxicity. No significant
activity or toxicity has been reported for the other metabolites.

Excretion

Epirubicin and its major
metabolites are eliminated through biliary excretion and, to a lesser extent,
by urinary excretion. Mass-balance data from 1 patient found about 60% of the
total radioactive dose in feces (34%) and urine (27%). These data are
consistent with those from 3 patients with extrahepatic obstruction and
percutaneous drainage, in whom approximately 35% and 20% of the administered
dose were recovered as epirubicin or its major metabolites in bile and urine,
respectively, in the 4 days after treatment.

Effect of Age

A population analysis of plasma
data from 36 cancer patients (13 males and 23 females, 20 to 73 years) showed
that age affects plasma clearance of epirubicin in female patients. The
predicted plasma clearance for a female patient of 70 years of age was about
35% lower than that for a female patient of 25 years of age. An insufficient
number of males > 50 years of age were included in the study to draw
conclusions about age-related alterations in clearance in males. Although a
lower ELLENCE starting dose does not appear necessary in elderly female
patients, and was not used in clinical trials, particular care should be taken
in monitoring toxicity when ELLENCE is administered to female patients > 70
years of age [see PATIENT INFORMATION].

Effect of Gender

In patients ≤ 50 years of
age, mean clearance values in adult male and female patients were similar. The
clearance of epirubicin is decreased in elderly women.

Effect of Race

The influence of race on the
pharmacokinetics of epirubicin has not been evaluated.

Effect of Hepatic Impairment

Epirubicin is eliminated by
both hepatic metabolism and biliary excretion and clearance is reduced in
patients with hepatic dysfunction. In a study of the effect of hepatic
dysfunction, patients with solid tumors were classified into 3 groups. Patients
in Group 1 (n=22) had serum AST (SGOT) levels above the upper limit of normal
(median: 93 IU/L) and normal serum bilirubin levels (median: 0.5 mg/dL) and
were given ELLENCE doses of 12.5 to 90 mg/m² . Patients in Group 2
had alterations in both serum AST (median: 175 IU/L) and bilirubin levels
(median: 2.7 mg/dL) and were treated with an ELLENCE dose of 25 mg/m² (n=8).
Their pharmacokinetics were compared to those of patients with normal serum AST
and bilirubin values, who received ELLENCE doses of 12.5 to 120 mg/m² .
The median plasma clearance of epirubicin was decreased compared to patients
with normal hepatic function by about 30% in patients in Group 1 and by 50% in
patients in Group 2. Patients with more severe hepatic impairment have not been
evaluated [seeDOSAGE AND ADMINISTRATION, and WARNINGS AND
PRECAUTIONS].

Effect of Renal Impairment

No significant alterations in the pharmacokinetics of
epirubicin or its major metabolite, epirubicinol, have been observed in
patients with serum creatinine < 5 mg/dL. A 50% reduction in plasma
clearance was reported in four patients with serum creatinine ≥ 5 mg/dL [see
WARNINGS AND PRECAUTIONS and DOSING
AND ADMINISTRATION]. Patients on dialysis have not been studied.

Effect of Paclitaxel

The administration of paclitaxel (175-225 mg/m² as
a 3-hour infusion) immediately before or after epirubicin (90 mg/m² as
bolus) caused variable increases in the systemic exposure (mean AUC) of
epirubicin ranging from 5% to 109%. At same doses of epirubicin and paclitaxel,
the mean AUC of the inactive metabolites of epirubicin (epirubicinol and
7-deoxy-aglycone) increased by 120% and 70%, respectively, when paclitaxel was
immediately administered after epirubicin. Epirubicin had no effect on the
exposure of paclitaxel whether it was administered before or after paclitaxel.

Effect of Docetaxel

The administration of docetaxel (70 mg/m² as
1-hour infusion) immediately before or after epirubicin (90 mg/m² as
bolus) had no effect on the systemic exposure (mean AUC) of epirubicin.
However, the mean AUC of epirubicinol and 7-deoxy-aglycone increased by 22.5%
and 95%, respectively, when docetaxel was immediately administered after
epirubicin compared to epirubicin alone. Epirubicin had no effect on the
exposure of docetaxel whether it was administered before or after docetaxel.

Effect of Cimetidine

Coadministration of cimetidine (400 mg twice daily for 7
days starting 5 days before chemotherapy) increased the mean AUC of epirubicin
(100 mg/m²) by 50% and decreased its plasma clearance by 30% .

Drugs metabolized by cytochrome P-450 enzymes

No systematic in vitro or in vivo evaluation has been
performed to examine the potential for inhibition or induction by epirubicin of
oxidative cytochrome P-450 isoenzymes.

Clinical Studies

Adjuvant Treatment Of Breast Cancer

Two randomized, open-label, multicenter studies evaluated
the use of ELLENCE Injection 100 to 120 mg/m² in combination with
cyclophosphamide and fluorouracil for the adjuvant treatment of patients with
axillary-node positive breast cancer and no evidence of distant metastatic
disease (Stage II or III). Study MA-5 evaluated 120 mg/m² of ELLENCE
per course in combination with cyclophosphamide and fluorouracil (CEF-120
regimen). This study randomized premenopausal and perimenopausal women with one
or more positive lymph nodes to an ELLENCE-containing CEF-120 regimen or to a CMF
regimen. Study GFEA-05 evaluated the use of 100 mg/m² of ELLENCE per
course in combination with fluorouracil and cyclophosphamide (FEC-100). This
study randomized pre-and postmenopausal women to the FEC-100 regimen or to a
lower-dose FEC-50 regimen. In the GFEA-05 study, eligible patients were either
required to have ≥ 4 nodes involved with tumor or, if only 1 to 3 nodes
were positive, to have negative estrogen-and progesterone-receptors and a
histologic tumor grade of 2 or 3. A total of 1281 women participated in these
studies. Patients with T4 tumors were not eligible for either study. Table 5
shows the treatment regimens that the patients received. Relapse-free survival
was defined as time to occurrence of a local, regional, or distant recurrence,
or disease-related death.

Patients with contralateral breast cancer, second primary
malignancy, or death from causes other than breast cancer were censored at the
time of the last visit prior to these events.

Table 5: Treatment Regimens Used in Phase 3 Studies of
Patients with Early Breast Cancer

aIn women who underwent lumpectomy, breast irradiation was
to be administered after completion of study chemotherapy. bPatients also received prophylactic antibiotic therapy with
trimethoprim-sulfamethoxazole or fluoroquinolone for the duration of their
chemotherapy. cAll women were to receive breast irradiation after the completion
of chemotherapy.

In the MA-5 trial, the median
age of the study population was 45 years. Approximately 60% of patients had 1
to 3 involved nodes and approximately 40% had ≥ 4 nodes involved with
tumor. In the GFEA-05 study, the median age was 51 years and approximately half
of the patients were postmenopausal. About 17% of the study population had 1 to
3 positive nodes and 80% of patients had ≥ 4 involved lymph nodes.
Demographic and tumor characteristics were well-balanced between treatment arms
in each study.

Relapse-free survival (RFS) and
overall survival (OS) were analyzed using Kaplan-Meier methods in the
intent-to-treat (ITT) patient populations in each study. Results were initially
analyzed after up to 5 years of follow-up and these results are presented in
the text below and in Table 6. Results after up to 10 years of follow-up are
presented in Table 6. In Study MA-5, ELLENCE-containing combination therapy
(CEF-120) showed significantly longer RFS than CMF (5-year estimates were 62% versus
53%, stratified logrank for the overall RFS p=0.013). The estimated reduction
in the risk of relapse was 24% at 5 years. The OS was also greater for the
ELLENCE-containing CEF-120 regimen than for the CMF regimen (5-year estimate
77% versus 70%; stratified logrank for overall survival p=0.043; non-stratified
logrank p=0.13). The estimated reduction in the risk of death was 29% at 5
years.

In Study GFEA-05, patients
treated with the higher-dose ELLENCE regimen (FEC-100) had a significantly
longer 5-year RFS (estimated 65% versus 52%, logrank for the overall RFS
p=0.007) and OS (estimated 76% versus 65%, logrank for the overall survival p=0.007)
than patients given the lower dose regimen (FEC-50). The estimated reduction in
risk of relapse was 32% at 5 years. The estimated reduction in the risk of
death was 31% at 5 years. Results of follow-up up to 10 years (median follow-up
= 8.8 years and 8.3 years, respectively, for Study MA-5 and Study GFEA-05) are
presented in Table 6.

Although the trials were not
powered for subgroup analyses, in the MA-5 study, improvements in favor of
CEF-120 vs. CMF were observed, in RFS and OS both in patients with 1-3 node
positive and in those with > 4 node positive tumor involvement. In the
GFEA-05 study, improvements in RFS and OS were observed in both pre-and
postmenopausal women treated with FEC-100 compared to FEC-50.